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Angiotensin-II signaling in the pars reticulata GABA-ergic neurons in the substantia nigra and its implications in nigral neurotransmission




Singh, Maibam Ratan, author
Amberg, Gregory C., advisor
Vigh, Jozsef, committee member
Tsunoda, Susan, committee member
Tamkun, Michael, committee member
Garrity, Deborah, committee member

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Renin-Angiotensin-system is one of the most widely studied hormonal systems in the peripheral system and is primarily associated with the essential function of regulating blood pressure, fluid and electrolyte balance in the body. Most of the drugs used to treat hypertension currently are targeted towards one or more components of the RAS system. However, increasing studies have presented evidence of local RAS in tissues completely independent of the humoral system. In the CNS, in addition to highly vascularized areas in the brain lacking the blood-brain-barrier (BBB) such as the circumventricular organs, all RAS components have also been found in the brain regions inside the BBB and are suspected to be involved in neuronal differentiation, neurotransmission, and learning and memory. Increasing studies have reported the interaction of brain RAS with pathophysiological mechanisms of many neurological and psychiatric illnesses. However, this extrarenal effect of RAS is only beginning to gain some scientific attention, and the underlying mechanisms are far from elucidated. All the RAS components are strongly expressed in the midbrain, especially the substantia nigra. Accumulating evidence in recent years has implicated Angiotensin-II (Ang-II), the primary effector peptide of RAS, in the selective degeneration of dopaminergic neurons in the substantia nigra compacta (SNc) in animal models of Parkinson's disease. Ang-II is believed to induce G-protein signaling through Ang-II type 1 receptor (AT1-R) and increase cellular oxidative stress, intracellular calcium load and activate apoptotic pathways in SNc dopaminergic neurons. Interestingly, studies have also shown Ang-II mediated striatal dopamine release in rats. These studies suggest that Ang-II signaling can induce both intracellular effects and influence dopaminergic neuronal output in the midbrain. However, if Ang-II signaling exists in other neuronal cell types in the substantia nigra is not known. Substantia nigra is comprised of two primary cell types: dopaminergic and GABAergic neurons. The majority of dopaminergic neurons are located in the SNc, and the SNr is comprised of GABAergic projection neurons with few interspersed dopaminergic neurons. Besides being one of the major output neurons of basal ganglia, SNr GABAergic projection neurons also provide significant inhibitory input to the neighboring SNc dopaminergic neurons, not through a direct axonal projection like its other target areas but via its extensive network of axon collaterals. Inhibitory input from the SNr GABAergic neurons contributes to the essential balance between afferent excitatory and inhibitory inputs to SNc dopaminergic neurons that tightly regulates their cellular activity and output. Indeed, SNr GABAergic neurons are necessary for the voluntary control of movement and are implicated in basal ganglia dysfunctions associated with movement disorders such as Parkinson's disease. RAS components are also expressed in the SNr GABAergic neurons, but it is not known if Ang-II signaling exists in these cells and what effects it may have on intranigral neurotransmission and dopaminergic cell activity. Here we used a combination of electrophysiology, imaging, and optogenetics to characterize and investigate the role of Ang-II in local neurotransmission in the substantia nigra. We found a heterogeneous effect of Ang-II in the nigral dopaminergic and GABAergic neurons. Ang-II suppressed both electrically and light-evoked activity of SNr GABAergic neurons through a combination of mechanisms: enhancement of postsynaptic GABAa receptors and increasing the action potential duration. On the contrary, Ang-II had no noticeable direct effect on the activity of SNc dopaminergic neurons and its GABAa receptors. This provides the first evidence of novel Ang-II signaling in SNr GABAergic neurons and its heterogeneous effect in the two nigral cell types. Interestingly, in contrast to observed suppression of SNr GABAergic neuronal activity by Ang-II, under phasic photoactivation of SNr GABAergic neurons, Ang-II enhanced the feedforward inhibitory input to SNc dopaminergic neurons. This shows a non-linear effect of Ang-II on population output of nigral GABAergic neurons and may indicate the involvement of an intricate intranigral network formed by the axon collaterals of SNr GABAergic neurons that can further modulate its effect on postsynaptic targets.


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